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Key tumor suppressor genes inactivated by "greater promoter" methylation and somatic mutations in head and neck cancer.
- Source :
-
Epigenetics [Epigenetics] 2014 Jul; Vol. 9 (7), pp. 1031-46. Date of Electronic Publication: 2014 May 01. - Publication Year :
- 2014
-
Abstract
- Tumor suppressor genes (TSGs) are commonly inactivated by somatic mutation and/or promoter methylation; yet, recent high-throughput genomic studies have not identified key TSGs inactivated by both mechanisms. We pursued an integrated molecular analysis based on methylation binding domain sequencing (MBD-seq), 450K Methylation arrays, whole exome sequencing, and whole genome gene expression arrays in primary head and neck squamous cell carcinoma (HNSCC) tumors and matched uvulopalatopharyngoplasty tissue samples (UPPPs). We uncovered 186 downregulated genes harboring cancer specific promoter methylation including PAX1 and PAX5 and we identified 10 key tumor suppressor genes (GABRB3, HOXC12, PARP15, SLCO4C1, CDKN2A, PAX1, PIK3AP1, HOXC6, PLCB1, and ZIC4) inactivated by both promoter methylation and/or somatic mutation. Among the novel tumor suppressor genes discovered with dual mechanisms of inactivation, we found a high frequency of genomic and epigenomic alterations in the PAX gene family of transcription factors, which selectively impact canonical NOTCH and TP53 pathways to determine cell fate, cell survival, and genome maintenance. Our results highlight the importance of assessing TSGs at the genomic and epigenomic level to identify key pathways in HNSCC, deregulated by simultaneous promoter methylation and somatic mutations.
- Subjects :
- Carcinoma, Squamous Cell metabolism
Cell Line, Tumor
Cohort Studies
CpG Islands
Female
Head and Neck Neoplasms metabolism
Humans
Male
Mutation
PAX5 Transcription Factor genetics
PAX5 Transcription Factor metabolism
Paired Box Transcription Factors genetics
Paired Box Transcription Factors metabolism
Receptor, Notch1 genetics
Receptor, Notch1 metabolism
Tumor Suppressor Protein p53 genetics
Tumor Suppressor Protein p53 metabolism
Carcinoma, Squamous Cell genetics
DNA Methylation
Gene Silencing
Genes, Tumor Suppressor
Head and Neck Neoplasms genetics
Promoter Regions, Genetic
Subjects
Details
- Language :
- English
- ISSN :
- 1559-2308
- Volume :
- 9
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Epigenetics
- Publication Type :
- Academic Journal
- Accession number :
- 24786473
- Full Text :
- https://doi.org/10.4161/epi.29025